Where the metabolome meets the microbiome for pancreatic cancer detection
Authors: Lucy Oldfield, Eithne Costello
Journal: Cell Reports Medicine (2023)

Risk prediction tools for pancreatic cancer are urgently sought to facilitate screening. Irajizad et al.1Irajizad E. Kenney A. Tang T. Vykoukal J. Wu R. Murage E. et al.A blood-based metabolite panel predictive of risk for pancreatic cancer.Cell Rep Med. 2023; 4: 101194Google Scholar describe the performance of a risk predication model based on circulating microbial- and non-microbial metabolites for assessment of 5-year pancreatic cancer risk. Risk prediction tools for pancreatic cancer are urgently sought to facilitate screening. Irajizad et al.1Irajizad E. Kenney A. Tang T. Vykoukal J. Wu R. Murage E. et al.A blood-based metabolite panel predictive of risk for pancreatic cancer.Cell Rep Med. 2023; 4: 101194Google Scholar describe the performance of a risk predication model based on circulating microbial- and non-microbial metabolites for assessment of 5-year pancreatic cancer risk. Pancreatic cancer is a leading cause of cancer deaths, and among the most lethal of the common cancers.2Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.CA. Cancer J. Clin. 2021; 71: 209-249Crossref PubMed Scopus (37821) Google Scholar Diagnosis most frequently occurs when the disease is at a late or incurable stage, leaving up to 85% of patients ineligible for potentially curative surgery. Earlier pancreatic cancer diagnosis is accompanied by better outcomes, and screening could play an important role in enabling earlier detection.3Pereira S.P. Oldfield L. Ney A. Hart P.A. Keane M.G. Pandol S.J. Li D. Greenhalf W. Jeon C.Y. Koay E.J. et al.Early detection of pancreatic cancer.Lancet. Gastroenterol. Hepatol. 2020; 5: 698-710Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar However, given the low incidence of pancreatic cancer, screening of asymptomatic adults with current screening modalities would yield an excessively high ratio of false positives to true positives. Consequently, strategies aimed at identifying those individuals at the highest risk of pancreatic cancer who would benefit from screening are sought. Evidence underpinning the contribution of microbiota to gastrointestinal cancer initiation and progression is persuasive.4Johnston C.D. Bullman S. The tumour-associated microbiome.Nat. Rev. Gastroenterol. Hepatol. 2022; 19: 347-348Crossref Scopus (2) Google Scholar This has led researchers to investigate whether alterations in an individual's microbiome could facilitate pancreatic cancer diagnosis.5Miyabayashi K. Ijichi H. Fujishiro M. The Role of the Microbiome in Pancreatic Cancer.Cancers. 2022; 144479Crossref Scopus (6) Google Scholar Equally, developments in the detection and quantification of metabolites have enabled the evaluation of blood-borne metabolites predictive of the presence of pancreatic cancer.6Wang S. Li M. Yan L. He M. Lin H. Xu Y. Wan Q. Qin G. Chen G. Xu M. et al.Metabolomics study reveals systematic metabolic dysregulation and early detection markers associated with incident pancreatic cancer.Int. J. Cancer. 2022; 150: 1091-1100Crossref Scopus (5) Google Scholar Possibilities surrounding the interrogation of the vast microbial metabolome creates exciting opportunities for early cancer detection. In their paper, Irajizad and colleagues1Irajizad E. Kenney A. Tang T. Vykoukal J. Wu R. Murage E. et al.A blood-based metabolite panel predictive of risk for pancreatic cancer.Cell Rep Med. 2023; 4: 101194Google Scholar undertook metabolomics to investigate the association between circulating microbial-related metabolites and risk of pancreatic cancer. Using sera from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial cohort7Gohagan J.K. Prorok P.C. Hayes R.B. Kramer B.S. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Project TeamThe Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status.Control. Clin. Trials. 2000; 21 (251s–72s)Google Scholar including 172 collected within 5 years prior to pancreatic cancer diagnosis and 863 matched non-case controls, the authors quantified a total of 14 microbial-related metabolites. Of these, indoleacrylic acid, trimethylamine N-oxide (TMAO), and indole-derivative 2 exhibited adjusted odds ratios (ORs) of ≥1.2 per unit standard deviation (SD) increase for risk prediction of pancreatic cancer. Both TMAO and indoleacrylic acid are associated with bacterial populations reported to have relevance in pancreatic cancer. Moreover, elevated levels of intracystic TMAO have been found in patients with intraductal papillary mucinous neoplasms (IPMNs).8Morgell A. Reisz J.A. Ateeb Z. Davanian H. Reinsbach S.E. Halimi A. Gaiser R. Valente R. Arnelo U. Chiaro M.D. et al.Metabolic characterization of plasma and cyst fluid from cystic precursors to pancreatic cancer patients reveal metabolic signatures of bacterial infection.medRxiv. 2020; 2020.11.03.20225524Google Scholar The presence of elevated levels of microbial-metabolites and bacterial DNA in IPMN, both with high-grade dysplasia and with cancer, is of interest and raises hopes for their exploitation in future early detection strategies. Irajizad et al.1Irajizad E. Kenney A. Tang T. Vykoukal J. Wu R. Murage E. et al.A blood-based metabolite panel predictive of risk for pancreatic cancer.Cell Rep Med. 2023; 4: 101194Google Scholar sought to increase the predictive performance of individual metabolite candidates via their combined contributions. The authors apply a number of models to assess the performance of TMAO, indoleacrylic acid, and indole-derivative 2 (the 3 metabolites exhibiting the highest ORs for 5-year risk of pancreatic cancer) as components of as 3-marker metabolite panel. The challenges facing development and validation of biomarker-based risk prediction models are considerable and worth highlighting. It is essential to follow a rigorous pipeline of training and testing, with careful selection of relevant modeling methods and constant consideration of the biological question. Using a robust biomarker pipeline, Irajizad et al. found that a LASSO regression model achieved the highest performance, with the combined 3-marker microbial panel demonstrating an increase in the 5-year probability of pancreatic cancer. In a Test Set, the 3-marker microbial panel yielded a similar performance for 5- and 2-year predictive risk of pancreatic cancer, with ORs of 1.72 and 1.43, respectively. Of note, although diabetes is a frequent characteristic of pancreatic cancer (occurring in 40–50% of cases), diabetes status did not confound the predictive performance of the 3-marker microbial panel. Diabetes status is commonly under-reported in historic cohorts and caution should be taken in evaluating its contribution to outcomes where clinical measurement is not available. Individuals with chronic pancreatitis (CP) also comprise an important control group in the evaluation of risk prediction for pancreatic cancer. To this end, in an independent set comprising samples from CP and pancreatic cancer, the 3-marker panel generated ORs of 2.83, 1.55, and 2.07 per unit increase for probability of CP, pancreatic cancer, or for pancreatic disease (CP or cancer), respectively, when compared to healthy controls. The influence of CP in enhancing the performance of the panel here is interesting and serves to exemplify the necessity of including CP as a control group in analyses of this type. Finally, Irajizad et al.1Irajizad E. Kenney A. Tang T. Vykoukal J. Wu R. Murage E. et al.A blood-based metabolite panel predictive of risk for pancreatic cancer.Cell Rep Med. 2023; 4: 101194Google Scholar evaluated the complementarity of non-microbial-related metabolites in combination with the tumor marker CA19-9 to enhance the performance of the microbiome-related metabolite panel. Of 1,009 non-microbial metabolites quantified in a PLCO sample set, five (cholesterol glucuronide, 2-hydroxyglutarate, galactosamine, glucose, and erythritol) had statistically significant adjusted ORs in independent assessment. In combination, the non-microbial and microbial metabolite panels demonstrated enhanced performance with an AUC of 0.79 and OR of 3.13 per unit SD for 5-year risk of pancreatic cancer. Further enhancement in performance was achieved through the inclusion of CA19-9 with an AUC of 0.84 and OR of 9.67 per unit SD increase for 5-year risk of pancreatic cancer. Biomarker studies for early pancreatic cancer detection frequently use samples from patients already diagnosed with cancer. Those studies leave open the question of whether reported alterations in biomarker levels would have been observed in the months and years prior to cancer diagnosis. Cohorts such as the PLCO cohort used by Irajizad et al.,1Irajizad E. Kenney A. Tang T. Vykoukal J. Wu R. Murage E. et al.A blood-based metabolite panel predictive of risk for pancreatic cancer.Cell Rep Med. 2023; 4: 101194Google Scholar where samples were collected from individuals who subsequently incurred a diagnosis of pancreatic cancer, are invaluable for the discovery and validation of early cancer biomarkers. Moreover, pre-diagnostic cohorts, for example those being assembled explicitly for the earlier detection of pancreatic cancer,9Chari S.T. Maitra A. Matrisian L.M. Shrader E.E. Wu B.U. Kambadakone A. Zhao Y.Q. Kenner B. Rinaudo J.A.S. Srivastava S. et al.Early Detection Initiative: A randomized controlled trial of algorithm-based screening in patients with new onset hyperglycemia and diabetes for early detection of pancreatic ductal adenocarcinoma.Contemp. Clin. Trials. 2022; 113106659Crossref PubMed Scopus (10) Google Scholar,10Oldfield L. Stott M. Hanson R. Jackson R.J. Reynolds W. Chandran-Gorner V. Van Der Meer R. Alison L. Tejeiro R. Purewal T. et al.United Kingdom Early Detection Initiative (UK-EDI): protocol for establishing a national multicentre cohort of individuals with new-onset diabetes for early detection of pancreatic cancer.BMJ Open. 2022; 12e068010Crossref Scopus (2) Google Scholar will in future provide bespoke samples tailored for this purpose. In summary, pancreatic cancer remains one of the major cancers for which there is no adult population-wide screening strategy. This poses a significant challenge to the scientific and healthcare community. While it remains unclear whether bacterial populations characterizing the pancreatic tumor microbiome are causative or simply bystanders, Irajizad and colleagues demonstrate the potential use of circulating microbial metabolites as indicators of an individual's risk of pancreatic cancer. The authors declare no competing interests. A blood-based metabolomic signature predictive of risk for pancreatic cancerIrajizad et al.Cell Reports MedicineSeptember 19, 2023In BriefIrajizad et al. report a blood-based metabolite panel that identifies individuals at high risk of developing pancreatic cancer within 5 years of blood draw. The metabolite panel provides a potential tool to identify individuals at high risk of pancreatic cancer who would benefit from surveillance and/or from potential cancer interception strategies. Full-Text PDF Open Access